Non-aqueous liquid nimodipine compositions

ABSTRACT

Non-aqueous liquid compositions comprising nimodipine having improved stability over aqueous compositions comprising nimodipine are provided herein. Methods of improving neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured intracranial berry aneurysms with the non-aqueous liquid compositions of the present invention are also detailed herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/621,953, filed Jan. 25, 2018, the contents of which are incorporatedby reference in their entirety.

FIELD OF THE INVENTION

The present invention relates generally to non-aqueous liquid nimodipinecompositions with improved stability compared to aqueous compositionscomprising nimodipine. The present invention also generally relates tomethods of treating conditions for which nimodipine is indicatedcomprising administering the non-aqueous liquid nimodipine compositionto a patient in need thereof.

BACKGROUND OF THE INVENTION

Nimodipine is a dihydropyridine derivative calcium channel blockerindicated for the improvement of neurological outcome by reducing theincidence and severity of ischemic deficits in patients withsubarachnoid hemorrhage (SAH) from ruptured intracranial berry aneurysmsregardless of their post-ictus neurological condition (i.e., Hunt andHess Grades I-V). Nimodipine has the chemical name1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate andthe structure shown below:

NIMOTOP® (Bayer Pharmaceuticals Corp.) is a liquid-filled capsuleformulation of nimodipine for oral dosing. Each NIMOTOP® capsulecontains 30 mg of nimodipine and is commonly administered in atwo-capsule 60 mg dose.

The prescribing information for NIMOTOP® states that, if the capsulecannot be swallowed (e.g., at the time of surgery) or if the patient isunconscious, a hole should be made in both ends of the capsule with an18 gauge needle, and the contents of the capsule extracted into asyringe. To help minimize administration errors, it is recommended thatthe syringe be labeled “Not for IV Use”. The contents should then beemptied into the patient's in situ naso-gastric tube and washed down thetube with 30 mL of normal saline (0.9%).

In addition to this method of delivery being cumbersome and timeconsuming, it is also dependent on the ability of the particularpractitioner. It is possible that the practitioner extracts less thanthe full amount of the liquid dose from the capsule, leading to underdosing and insufficient treatment.

NYMALIZE® (Arbor Pharmaceuticals, LLC) was the first marketed oralnimodipine solution, eliminating the need for needle extraction ofnimodipine from capsules for patients that cannot consume capsules.NYMALIZE® is supplied in bottles that should be stored between to 25° C.(68° F. to 77° F.), protected from light, and un-refrigerated. Therecommended dose is 20 mL (containing 60 mg of nimodipine) every 4 hoursfor 21 consecutive days. The inactive ingredients in NYMALIZE® areethanol, glycerin, methylparaben, polyethylene glycol, sodium phosphatemonobasic and water (about 20% by volume).

It has been found that NYMALIZE® slowly degrades under certainconditions (e.g., elevated temperature and humidity). One of thedegradants includes nimodipine related compound A, (2-Methoxyethyl1-methylethyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate)having the following structure:

Accordingly, there remains a need for liquid nimodipine formulationswith improved stability and decreased degradation.

SUMMARY OF THE INVENTION

The present invention generally relates to novel non-aqueous liquidpharmaceutical compositions containing nimodipine that have improvedshelf-life and decreased nimodipine-related degradation compared toexisting aqueous liquid pharmaceutical compositions.

In one aspect, the present invention provides a non-aqueous liquidcomposition comprising nimodipine. In one embodiment, the non-aqueousliquid composition comprises nimodipine and a solvent comprisingethanol, wherein the ethanol is present in the composition in an amountof about 1% or less by weight.

In one embodiment, the present invention provides a non-aqueous liquidcomposition comprising nimodipine in a concentration greater than about3 mg/mL, more preferably about 6 mg/mL or greater, still more preferablyabout 12 mg/mL or greater.

In still another embodiment, the present invention provides anon-aqueous liquid composition comprising nimodipine, wherein about 5%or less nimodipine degradation is observed over a period of at leastthree months when exposed to 40° C. and 75% relative humidity.

In certain embodiments, the present invention provides a non-aqueousliquid composition comprising nimodipine, wherein about 4.5% or lessnimodipine degradation is observed over a period of at least threemonths when exposed to 40° C. and 75% relative humidity.

In another embodiment, the present invention provides a non-aqueousliquid composition comprising nimodipine and about 1.2% or lessnimodipine related compound A when the composition is exposed to 40° C.and 75% relative humidity over a period of at least three months.

In a particular embodiment, the present invention provides a non-aqueousliquid composition comprising nimodipine and about 0.01% to about 1.2%nimodipine related compound A when the composition is exposed to 40° C.and 75% relative humidity over a period of at least three months, andmore particularly, about 0.10% to about 0.8% nimodipine related compoundA.

In one embodiment, the present invention provides a non-aqueous liquidcomposition comprising nimodipine and at least about 90% less nimodipinerelated compound A than NYMALIZE® when both compositions area exposed to40° C. and 75% relative humidity over a period of at least three months,and more particularly, at least about 75% less, at least about 60% lessor at least about 50% less nimodipine related compound A than NYMALIZE®.

In one embodiment, the present invention provides a non-aqueous liquidcomposition comprising nimodipine and substantially no nimodipinerelated compound A. In one embodiment, the present invention provides anon-aqueous liquid composition comprising nimodipine, wherein about 2.0%or less total impurities are observed over a period of at least threemonths when exposed to 40° C. and 75% relative humidity.

In another embodiment, the present invention provides a non-aqueousliquid composition comprising nimodipine, wherein about 1.0% or lesstotal impurities are observed over a period of at least three monthswhen exposed to 40° C. and 75% relative humidity.

In a particular embodiment, the present invention provides a non-aqueousliquid composition comprising nimodipine, wherein about 0.01% to about2.0% total impurities are observed over a period of at least threemonths when exposed to 40° C. and 75% relative humidity, and moreparticularly, about 0.1% and about 1.9% total impurities.

In one embodiment, the present invention provides a non-aqueous liquidcomposition comprising nimodipine and at least about 90% less totalimpurities than NYMALIZE® when both compositions re exposed to 40° C.and 75% relative humidity over a period of at least three months, andmore particularly, at least about 75% less, at least about 60% less orat least about 50% less total impurities than NYMALIZE®.

In one embodiment, the present invention provides a non-aqueous liquidcomposition comprising nimodipine and substantially no total impuritiesare observed over a period of at least three months when exposed to 40°C. and 75% relative humidity.

In another embodiment, the present invention provides a non-aqueousliquid composition comprising nimodipine and about 0.3% or lessnimodipine related compound A over a period of at least three monthswhen exposed to 25° C. and 60% relative humidity.

In another embodiment, the present invention provides a non-aqueousliquid composition comprising nimodipine and about 0.01% to about 0.3%nimodipine related compound A over a period of at least three monthswhen exposed to 25° C. and 60% relative humidity, or more particularly,about 0.01% and about 0.1% nimodipine related compound A.

In one embodiment, the present invention provides a non-aqueous liquidcomposition comprising nimodipine and at least about 90% less nimodipinerelated compound A than NYMALIZE® when both compositions are exposed to25° C. and 60% relative humidity over a period of at least three months,and more particularly, at least about 85% less, at least about 69% less75% less, at least about 60% less or at least about 50% less nimodipinerelated compound A than NYMALIZE®.

in a particular embodiment, the non-aqueous liquid composition comprisesnimodipine and substantially no nimodipine related compound A when thecomposition is exposed to 25° C. and 60% relative humidity over a periodof at least three months.

In another embodiment, the present invention provides a non-aqueousliquid composition comprising nimodipine, wherein about 0.4% or lesstotal impurities are observed over a period of at least three monthswhen exposed to 25° C. and 60% relative humidity. In a particularembodiment, the present invention provides a non-aqueous liquidcomposition comprising nimodipine, wherein about 0.01% to about 0.4%total impurities are observed over a period of at least three monthswhen exposed to 25° C. and 60% relative humidity, and more particularly,about 0.1% and about 0.4% total impurities.

In one embodiment, the present invention provides a non-aqueous liquidcomposition comprising nimodipine and at least about 90% less totalimpurities related than NYMALIZE® when both compositions are exposed to25° C. and 75% relative humidity over a period of at least three months,and more particularly, at least about 85% less, at least about 60% less75% less, at least about 60% less or at least about 50% less totalimpurities than NYMALIZE®.

In one embodiment, the present invention provides a non-aqueous liquidcomposition comprising nimodipine and substantially no total impuritiesare observed over a period of at least three months when exposed to 25°C. and 60% relative humidity.

In another aspect, the present invention provides a method of treatingdisorders, or symptoms associated with disorders for which nimodipineprovides a therapeutic effect.

In one embodiment, the present invention provides a method of reducingthe incidence and severity of ischemic deficits in patients withsubarachnoid hemorrhage from ruptured intracranial berry aneurysmscomprising administering to a patient in need thereof an effectiveamount of a non-aqueous liquid composition described herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to non-aqueous liquid compositionscomprising nimodipine. The liquid compositions of the invention haveimproved stability and decreased degradants compared to existing aqueousliquid pharmaceutical compositions, e.g. NYMALIZE®. When comparisons aremade, it is understood to be under the same or similar conditions.

I. Definitions

Pharmaceutical compositions and medicaments may be described as mixturesof two or more components “by volume,” which is herein defined as thevolume due to one component divided by the volume of all components ofthe pharmaceutical composition. This ratio may be converted to orreported as a percentage of the total composition volume. Such aquantity may also be indicated by “v/v” or “percent v/v.” Similarly, thephrase “by weight” describes the weight due to one component divided bythe weight of all components of the composition. This ratio may beconverted to or reported as a percentage of the total compositionweight. Such a quantity may also be indicated by “w/w” or “percent w/w.”

As used herein, the term “degradation product” refers to impuritiesresulting from chemical changes that occur during drug manufacturing,storage and/or transportation in response to changes in light,temperature, pH, and humidity, or due to inherent characteristics of theactive pharmaceutical substance, such as their reaction with excipientsor on contact with the packaging. For example, the degradation productsof nimodipine include: (1) 2-methoxyethyl1-methylethyl-2,6-dimethyl4-(3-nitrophenyl) pyridine-3,5-dicarboxylate(i.e., nimodipine related compound A); (2) bis(1-methylethyl)-2,6-dimethyl-4-(3-nitrophenyl),1,4-dihydro-pyridine-3,5-dicarboxy-late and (3) bis(2-methoxyethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.

As used herein, the term “dosage unit” or “unit dose” (usedinterchangeably) refers to one dose of the non-aqueous liquidcomposition of the present invention, as administered to the patient.For example, multiple dosage units can be present when the non-aqueousliquid composition of the present invention is stored in a bottle. Afraction of that bottle, i.e. a single dosage unit, is administered tothe patient at a time. In the current NYMALIZE® formulation, a dosageunit is 20 mL (containing 60 mg of nimodipine).

As used herein, the term “effective amount” refers the amount of activeagent present in the composition that is needed to provide a desiredlevel of active agent in the bloodstream or the target tissue. Theprecise amount will depend upon numerous factors and can readily bedetermined by one skilled in the art, based upon the informationprovided herein and available in the relevant literature.

As used herein, the term “nimodipine” includes the racemate, othermixtures of (+)- and (−)-isomers, and single enantiomers, but may bespecifically set forth as the racemate, (+)-isomer, (−)-isomer, or anymixture of both (+)- and (−)-isomers.

As used herein, the term “non-aqueous” refers to compositions containingsubstantially no water, i.e. less than 1% by volume. In a particularembodiment, the non-aqueous liquid compositions of the present inventioncontain no water.

As used herein, the term “patient” refers to a living organism sufferingfrom or prone to a condition that can be prevented or treated byadministration of a composition described herein, and includes bothhumans and animals. In one embodiment, the patient is a human patient.

As used herein, the terms “pharmaceutically acceptable excipient” or“pharmaceutically acceptable carrier” refers to an excipient that can beincluded in the compositions of the invention and that causes nosignificant adverse toxicological effects to the patient to which thecomposition is administered.

As used herein, the term “stable” or “stabilized” with respect to acomposition is one in which the active ingredient retains its chemicalstability, physical stability, microbiological stability, therapeuticstability and/or toxicological stability. Stability may be measuredunder a variety of conditions including long-term stability,intermediate stability, accelerated stability, real-time stability or acombination thereof. In real-time stability testing, a product is storedat recommended storage conditions and monitored until it fails thespecification. In accelerated stability tests, a product is stored atelevated stress conditions (such as temperature, humidity, and pH).Degradation at the recommended storage conditions can be predicted usingknown relationships between the acceleration factor and the degradationrate.

As used herein, the term “substantially no nimodipine related compoundA” refers to an undetectable amount of nimodipine related compound A asmeasured by HPLC.

As used herein, the term “treat” or “treating” of a disease stateincludes: 1) inhibiting the disease state, i.e., arresting thedevelopment of the disease state or its clinical symptoms; 2)attenuating the disease state, i.e. reducing the number or intensity ofone or more symptoms associated with the disease state, such that one ormore symptoms is reduced but may, or may not be completely eliminated;and/or 3) relieving the disease state, i.e., causing temporary orpermanent regression of the disease state or its clinical symptoms.

II. Compositions

In one embodiment, the present invention provides non-aqueous liquidcompositions comprising nimodipine. As the non-aqueous liquidcompositions contain substantially no water, one or more solvents isused to formulate the nimodipine.

Exemplary solvents include, but are not limited to, glycerol,dimethylsulfoxide, N-methylpyrrolidone, dimethyl acetamide (DMA),dimethyl formamide, glycerol formal, ethoxy diglycol, triethylene glycoldimethyl ether, triacetin, diacetin, corn oil, acetyl triethyl citrate(ATC), ethyl lactate, polyglycolated capryl glycerides butyrolactone,dimethyl isosorbide, benzyl alcohol, ethanol, isopropyl alcohol,polyethylene glycol of various molecular weights, including but notlimited to PEG 300 and PEG 400, or propylene glycol, or a mixture of oneor more thereof.

In a particular embodiment, the solvent comprises polyethylene glycol,ethanol and glycerol.

The amount of solvent in the non-aqueous liquid compositions can vary.In one embodiment, ethanol comprises from about 0.1% (w/v) to about 1%(w/v), such as, for example, from about 0.1% to about 0.5%. Polyethyleneglycol may comprise from about 50% to about 75% (w/v) of the non-aqueousliquid composition, such as, for example, from about 60% to about 70%.Glycerin may comprise from about 25% to about 60% (w/v) of thenon-aqueous liquid composition, such as, for example, from about 40% toabout 50%.

In one embodiment, the non-aqueous liquid formulations consistsessentially of nimodipine and one or more solvents listed above.

In other embodiments, the non-aqueous liquid formulation comprises oneor more additional excipients, such as, for example, buffering agentsand/or preservatives.

Exemplary buffering agents include, but are not limited to, benzoicacid, phosphoric acid, tartaric acids, lactic acid, succinic acid,citric acid, acetic acid, ascorbic acid, aspartic acid, hydrochloricacid, sulfuric acid, glutamic acid, and salts thereof. In a particularembodiment, the buffering agent comprises sodium benzoate and benzoicacid.

In one embodiment, the preservative comprises from about 0.01% to about0.1% (w/v) of the non-aqueous liquid formulation.

The preservative can be from the paraben family. Exemplary parabenpreservatives include, but are not limited to, methylparaben,propylparaben, ethylparaben, butylparaben, isobutylparaben,isopropylparaben, benzylparaben, sodium salts of the referencedparabens, or mixtures of thereof.

The preservative can be a sorbate (salt of sorbic acid and/or sorbicacid), benzoate (salt of benzoic acid and/or benzoic acid), sulfurdioxide, sulfite, nitrite, nitrate, lactic acid, propionic acid,propionate, ascorbic acid, ascorbate, butylated hydroxytoluene orcombinations thereof. In one embodiment, the preservative comprisessodium benzoate and benzoic acid.

In one embodiment, the preservative comprises from about 0.01% to about1% (w/v) of the non-aqueous liquid formulation.

In still another embodiment, the non-aqueous liquid formulationcomprises an agent that functions as both a buffer and a preservative,e.g. sodium benzoate and benzoic acid.

The non-aqueous liquid composition comprises nimodipine in an effectiveamount per dosage unit. In one embodiment, the non-aqueous liquidcomposition comprises from about 10 mg to about 100 mg nimodipine perdosage unit, such as, for example, at least about 30 mg, at least about40 mg, at least about 50 mg, at least about 60 mg or at least about 70mg. In a particular embodiment, the non-aqueous liquid compositioncomprises about 60 mg or more nimodipine per dosage unit. In a moreparticular embodiment, the non-aqueous liquid composition comprisesabout 60 mg nimodipine per dosage unit.

The amount of solvent in the dosage unit can vary. In one embodiment,the non-aqueous liquid composition comprises from about 1 mL to about 20mL solvent per dosage unit, such as, for example, from about 5 mL toabout 20 mL, from about 5 mL to about 15 mL, from about 5 mL to about 10mL, from about 10 mL to about 20 mL, from about 10 mL to about 15 mL orfrom about 15 mL to about 20 mL. In a particular embodiment, thenon-aqueous liquid composition comprises about 5 mL of solvent perdosage unit. In another particular embodiment, the non-aqueous liquidcomposition comprises about 10 mL of solvent per dosage unit. In stillanother particular embodiment, the non-aqueous liquid compositioncomprises about 20 mL of solvent per dosage unit.

The concentration of nimodipine in NYMALIZE® (60 mg/20 mL) is 3 mg/mL.The non-aqueous liquid composition of the present invention allows useof a higher nimodipine concentrations per dose, thereby lowering apatient's daily intake of the liquid composition compared to NYMALIZE®.

Accordingly, the concentration of nimodipine in the non-aqueous liquidcomposition of the present invention is greater than about 3 mg/mL, suchas, for example, at least about 4 mg/mL, at least about 5 mg/mL, atleast about 6 mg/mL, at least about 7 mg/mL, at least about 8 mg/mL, atleast about 9 mg/mL, at least about 10 mg/mL, at least about 11 mg/mL,at least about 12 mg/mL, at least about 13 mg/mL, at least about 14mg/mL, at least about 15 mg/mL, at least about 16 mg/mL, at least about17 mg/mL, at least about 18 mg/mL, at least about 19 mg/mL or at leastabout 20 mg/mL.

In another embodiment, the concentration of nimodipine in thenon-aqueous liquid composition is between any of the concentrationsrecited above, such as, for example, from about 5 mg/mL to about 20mg/mL, from about 5 mg/mL to about 15 mg/mL, from about 5 mg/mL to about10 mg/mL, about 10 mg/mL to about 20 mg/mL, from about 10 mg/mL to about15 mg/mL and from about 15 mg/mL to about 20 mg/mL.

In a particular embodiment, the concentration of nimodipine in thenon-aqueous liquid composition of the present invention is about 3 mg/mLto about 10 mg/mL, about 3 mg/mL to about 9 mg/mL, about 3 mg/mL toabout 8 mg/mL, about 3 mg/mL to about 7 mg/mL, about 3 mg/mL to about 6mg/mL, about 3 mg/mL to about 5 mg/mL, or about 3 mg/mL to about 4mg/mL.

In another particular embodiment, the concentration of nimodipine in thenon-aqueous liquid composition of the present invention is about 4 mg/mLto about 10 mg/mL, about 4 mg/mL to about 9 mg/mL, about 4 mg/mL toabout 8 mg/mL, about 4 mg/mL to about 7 mg/mL, about 4 mg/mL to about 6mg/mL or about 4 mg/mL to about 5 mg/mL.

In yet another particular embodiment, the concentration of nimodipine inthe non-aqueous liquid composition of the present invention is about 5mg/mL to about 10 mg/mL, about 5 mg/mL to about 9 mg/mL, about 5 mg/mLto about 8 mg/mL, about 5 mg/mL to about 7 mg/mL, or about 5 mg/mL toabout 6 mg/mL.

In another particular embodiment, the concentration of nimodipine in thenon-aqueous liquid composition of the present invention is about 6 mg/mLto about 10 mg/mL, about 6 mg/mL to about 9 mg/mL, about 6 mg/mL toabout 8 mg/mL or about 6mg/mL to about 7 mg/mL.

In one embodiment, the concentration of nimodipine in the non-aqueousliquid composition of the present invention is about 7 mg/mL to about 10mg/mL, about 7 mg/mL to about 9 mg/mL or about 7 mg/mL to about 8 mg/mL.

In another embodiment, the concentration of nimodipine in thenon-aqueous liquid composition of the present invention is about 8 mg/mLto about 10 mg/mL or about 8 mg/mL to about 9 mg/mL

In still another embodiment, the concentration of nimodipine in thenon-aqueous liquid composition is any of the concentrations recitedabove, such as, for example, about 4 mg/mL, about 5 mg/mL, about 6mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL,about 11 mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL orabout 20 mg/mL.

In preferred embodiments, a dosage unit of the non-aqueous liquidcomposition comprises 60 mg nimodipine in about 5 mL solvent to about 10mL of solvent, such as, for example, about 5 mL of solvent (12 mg/mL) orabout 10 mL (6 mg/mL).

The density of the non-aqueous liquid composition may vary. In oneembodiment, the density is between about 0.8 and about 1.8, such as, forexample, between about 0.8 and about 1.0, about 1.0 and about 1.2, about1.2 and about 1.4, about 1.4 and about 1.6, about 1.6 and about 1.8. Inanother embodiment, the density is about 0.8, about 0.9, about 1.0,about 1.1, about 1.2, 1.3, about 1.4, about 1.5, about 1.6, about 1.7 orabout 1.0.

In a particular embodiment, the density is between 1.10 and about 1.26,more particularly, about 1.12 and about 1.24, about 1.14 and about 1.22,about 1.16 and about 1.20, and even more particularly, about 1.10, about1.11, about 1.12, about 1.13, about 1.14, about 1.15, about 1.16, about1.17, about 1.18, about 1.19, about 1.20, about 1.21, about 1.22, about1.23, about 1.24, about 1.25 or about 1.26.

The non-aqueous liquid compositions of the present invention do notexhibit substantial nimodipine degradation when exposed to certain studyconditions. Stability may be measured by any suitable method, e.g., byhigh-performance liquid chromatography (HPLC). In a particularembodiment, the non-aqueous liquid compositions of the present inventiondo not exhibit substantial nimodipine degradation under hydrolyticconditions, oxidative conditions, photolytic conditions, thermalconditions or combinations thereof. In another particular embodiment,the non-aqueous liquid compositions of the present invention do notexhibit substantial nimodipine degradation under forced stabilityconditions, accelerated stability conditions, real-time stabilityconditions or a combination thereof.

In some embodiments, the non-aqueous liquid compositions disclosedherein do not exhibit substantial degradation under acceleratedconditions (e.g. 40° C. and 75% relative humidity) for at least 3months, at least 6 months, at least 8 months, at least 10 months, atleast 12 months, or at least 24 months. Methods of measuring nimodipinedegradation are known to a person of skill in the art, e.g., monitoringthe amount of nimodipine in the non-aqueous liquid composition by HPLCover a period of time. An exemplary method is provided in Example 1infra.

In one embodiment, the non-aqueous liquid composition exhibits about 5%or less nimodipine degradation over at least a three month period whenexposed to 40° C. and 75% relative humidity, such as, for example, about4.5% or less, 4.0% or less, about 3.5% or less, about 3.0% or less,about 2.5% or less, about 2.0% or less, about 1.5% or less or about 1.0%or less.

In a particular embodiment, the non-aqueous liquid composition exhibitsabout 1.0% or less nimodipine degradation over at least a three monthperiod when exposed to 40° C. and 75% relative humidity, such as, forexample, about 0.90% or less, about 0.80% or less, about 0.70% or less,about 0.60% or less, about 0.50% or less, about 0.40% or less, about0.30% or less, about 0.20% or less or about 0.10% or less.

In one embodiment, the non-aqueous liquid composition comprises arelatively smaller amount of nimodipine degradation compared withNYMALIZE® over at least a three month period when exposed to 40° C. and75% relative humidity, i.e., less than about 5% degradation, from about3% to about 4% degradation, from about 1% to about 2% degradation, from0.01% to about 1% degradation, from about 0.01% to about 0.9%degradation, from about 0.01% to about 0.8% degradation, from about0.01% to about 0.7% degradation, from about 0.01% to about 0.6%degradation, from about 0.01% to about 0.5% degradation, from about0.01% to about 0.4% degradation, from about 0.01% to about 0.3%degradation, from about 0.01% to about 0.2% degradation, from about0.01% to about 0.1% degradation and from about 0.01% to about 0.05%degradation.

In one embodiment, the non-aqueous liquid composition exhibits betweenabout 0.50% and about 4.0%, about 0.50% and about 0.35%, about 0.5% andabout 0.30%, about 0.50% and about 0.20%, about 0.50% and about 0.10%;about 0.10% and about 4.0%, about 1.0% and about 3.5%, about 1.0% andabout 3.0%, about 1.0% and about 2.5%, about 1.0% and about 2.0%, about1.5% and about 4.0%, about 1.5% and about 3.5%, about 1.5% and about3.0%, about 1.5% and about 2.5%, about 1.5% and about 2.0%, about 2.0%and about 2.5 nimodipine degradation over at least a three month periodwhen exposed to 40° C. and 75% relative humidity

In a particular embodiment, the non-aqueous liquid composition exhibitsabout 95% or less, about 90% or less, about 85% or less, about 80% orless, about 76% or less, about 70% or less, about 65% or less, 60% orless, about 55% or less, about 50% or less, about 45% or less, about 40%or less, about 35% or less, about 30% or less, about 25% or less, about20% or less, about 15% or less, about 10% or less nimodipine degradationthan NYMALIZE® over at least a three month period when exposed to 40° C.and 75% relative humidity.

In another particular embodiment, the non-aqueous liquid compositionexhibits about 1.0% to about 90%, about 1.0% and about 80%, about 1.0%and about 70%, about 1.0% and about 60%, about 1.0% and about 50%, about1.0% to about 40%, about 1.0% to about 30%, about 1.0% to about 20%,about 1.0% to about 10% or less nimodipine degradation than NYMALIZE®over at least a three month period when exposed to 40° C. and 75%relative humidity.

In another particular embodiment, the non-aqueous liquid compositionexhibits about 10% to about 90%, about 10% and about 80%, about 10% andabout 70%, about 10% and about 60%, about 10% and about 50%, about 10%to about 40%, about 10% to about 30%, or about 10% to about 20% lessnimodipine degradation than NYMALIZE® over at least a three month periodwhen exposed to 40° C. and 75% relative humidity.

In another particular embodiment, the non-aqueous liquid compositionexhibits about 20% to about 90%, about 20% and about 80%, about 20% andabout 70%, about 20% and about 60%, about 20% and about 50%, about 20%to about 40%, or about 20% to about 30% less nimodipine degradation thanNYMALIZE® over at least a three month period when exposed to 40° C. and75% relative humidity.

In yet another particular embodiment, the non-aqueous liquid compositionexhibits about 40 to about 70% or about 50 to about 60% less nimodipinedegradation than NYMALIZE® over at least a three month period whenexposed to 40° C. and 75% relative humidity.

One particular nimodipine degradation product that can be minimizedusing the non-aqueous liquid compositions of the present invention isnimodipine related compound A. In certain embodiments, the non-aqueousliquid composition comprises from 0.01% to about 1.5% nimodipine relatedcompound A over at least a three month period when exposed to 40° C. and75% relative humidity, such as, for example, from about 0.01% to about0.1% and from about 0.01% to about 0.05%.

In a particular embodiment, the non-aqueous liquid composition about1.9% or less nimodipine related compound A over at least a three monthperiod when exposed to 40° C. and 75% relative humidity, or moreparticularly, about 1.8% or less, about 1.7% or less, about 1.6% orless, about 1.5% or less, about 1.4% or less, about 1.3 or less, orabout 1.2% or less. In a particular embodiment, the non-aqueous liquidcomposition about 1.9% or less nimodipine related compound A over atleast six month period when exposed to 40° C. and 75% relative humidity

In a particular embodiment, the non-aqueous liquid composition about1.2% or less nimodipine related compound A over at least a three monthperiod when exposed to 40° C. and 75% relative humidity, or moreparticularly, about 1.0% or less, about 0.90% or less, about 0.80% orless, about 0.70% or less, about 0.60% or less, about 0.50% or less,about 0.40% or less, about 0.30% or less, about 0.20% or less, about0.10% or less about 0.08% or less, about 0.06% or less, about 0.04% orless, about 0.02% or less, or about 0.01% or less nimodipine relatedcompound A.

In one embodiment, the non-aqueous liquid composition comprises from0.01% to about 1.2% nimodipine related compound A over at least a threemonth period when exposed to 40° C. and 75% relative humidity, and moreparticularly, about 0.01% to about 1.0% , about 0.01% to about 0.20%,about 0.01% to about 0.40%, about 0.01 to about 0.60%, about 0.01% toabout 0.80%, about 0.01% to about 1.0%, about 0.01% to about 1.2%nimodipine related compound A.

In one embodiment, the non-aqueous liquid composition comprises from0.1% to about 1.2% nimodipine related compound A over at least a threemonth period when exposed to 40° C. and 75% relative humidity, and moreparticularly, about 0.1% to about 1.0%, about 0.1% to about 0.20%, about0.1% to about 0.40%, about 0.1 to about 0.60%, about 0.1% to about0.80%, about 0.1% to about 1.0%, about 0.1% to about 1.2% nimodipinerelated compound A.

In a particular embodiment, the non-aqueous liquid composition containssubstantially no nimodipine related compound A over at least a threemonth period when exposed to 40° C. and 75% relative humidity

In one embodiment, the non-aqueous liquid composition contains about100% or less, 95% or less, about 90% or less, about 85% or less, about80% or less, about 75% or less, about 70% or less, about 65% or less,about 60% or less, about 55% or less, about 50% or less, about 45% orless, about 40% or less, about 35% or less, about 30% or less, about 25%or less, about 20% or less, about 15% or less, or about 10% or lessnimodipine related compound A than NYMALIZE® over at least a three monthperiod when exposed to 40° C. and 75% relative humidity.

In a particular embodiment, the non-aqueous liquid composition containsbetween about 1.0% and about 90% less, about 1.0% and about 80% less,about 1.0% and 70%, about 1.0% and about 60%, about 1.0% and about 50%,about 1.0% and about 30%, about 1.0% and about 20%, about 1.0% and about10%, about 1.0% and about 5.0% less nimodipine related compound A thanNYMALIZE® over at least a three month period when exposed to 40° C. and75% relative humidity,

In a particular embodiment, the non-aqueous liquid composition containsbetween about 10% and about 90% less, about 10% and about 80% less,about 10% and 70%, about 10% and about 60%, about 10% and about 50%,about 10% and about 30%, about 10% and about 20%, about 20% and about90%, about 20% and about 80%, about 20% and about 70%, about 20% andabout 60%, about 20% and about 50%, about 20% and about 40%, about 20%and about 30%, about 30% and about 90%, about 30% and about 80%, about30% and about 70%, about 30% and about 60%, about 30% and about 50%, orabout 30% and about 40% less nimodipine related compound A thanNYMALIZE® over at least a three month period when exposed to 40° C. and75% relative humidity.

In one embodiment, the non-aqueous liquid compositions of the presentinvention comprises less than about 3.0% total impurities over at leasta three month period when exposed to 40° C. and 75% relative humiditysuch as, for example, about 2.9% or less, about 2.8% or less, about 2.6%or less, about 2.4% or less, about 2.2% or less, or about 2.0% or lesstotal impurities.

In one embodiment, the non-aqueous liquid compositions of the presentinvention comprises less than about 2.0% total impurities over at leasta three month period when exposed to 40° C. and 75% relative humiditysuch as, for example, about 1.9% or less, about 1.8% or less, about 1.6%or less, about 1.4% or less, about 1.2% or less, about 1.0% or less,about 0.8% or less or about 0.6%, about 0.4% or less or about 0.2% orless total impurities.

In a particular embodiment, the non-aqueous liquid compositions of thepresent invention comprises between about 0.1% and about 2.0% totalimpurities over at least a three month period when exposed to 40° C. and75% relative humidity, or more particularly, about 0.1% and about 1.8%,about 0.1% and about 1.6% total impurities, about 0.1% and about 1.4%,about 0.1% and about 1.2%, about 0.1% and 1.0%, about 0.1% and about0.8%, about 0.1% and about 0.6%, about 0.1% and about 0.4%, or about0.1% and about 0.2% total impurities.

In one embodiment, the non-aqueous liquid composition contains about100% or less, 95% or less, about 90% or less, about 85% or less, about80% or less, about 75% or less, about 70% or less, about 65% or less,about 60% or less, about 55% or less, about 50% or less, about 45% orless, about 40% or less, about 35% or less, about 30% or less, about 25%or less, about 20% or less, about 15% or less, or about 10% or lesstotal impurities than NYMALIZE® over at least a three month period whenexposed to 40° C. and 75% relative humidity.

In one embodiment, the non-aqueous liquid composition contains about1.0% and about 90% less, about 1.0% and about 80% less, about 1.0% and70%, about 1.0% and about 60%, about 1.0% and about 50%, about 1.0% andabout 30%, about 1.0% and about 20%, about 1.0% and about 10%, or about1.0% and about 5.0% less total impurities than NYMALIZE® over at least athree month period when exposed to 40° C. and 75% relative humidity.

In one embodiment, the non-aqueous liquid composition contains about 10%and about 90% less, about 10% and about 80% less, about 10% and 70%,about 10% and about 60%, about 10% and about 50%, about 10% and about30%, about 10% and about 20% less total impurities than NYMALIZE® overat least a three month period when exposed to 40° C. and 75% relativehumidity.

In one embodiment, the non-aqueous liquid composition contains about 20%and about 90% less, about 20% and about 80% less, about 20% and 70%,about 20% and about 60%, about 20% and about 50%, or bout 20% and about30% less total impurities than NYMALIZE® over at least a three monthperiod when exposed to 40° C. and 75% relative humidity.

In one embodiment, the non-aqueous liquid composition contains aboutbetween about 40 and about 70% or about 50 and about 60% less totalimpurities than NYMALIZE® over at least a three month period whenexposed to 40° C. and 75% relative humidity.

In one embodiment, the non-aqueous liquid compositions of the presentinvention comprises substantially no impurities over at least a threemonth period when exposed to 40° C. and 75% relative humidity.

In some embodiments, the non-aqueous liquid compositions disclosedherein do not exhibit substantial degradation under ambient conditions(e.g. 25° C. and 60% relative humidity) for at least 3 months, at least6 months, at least 8 months, at least 10 months, at least 12 months, orat least 24 months. In a particular embodiment, non-aqueous liquidcompositions disclosed herein do not exhibit substantial degradationunder ambient conditions (e.g. 25° C. and 60% relative humidity) about24 months or greater, such as, e.g., 26 months, 28 months, 30 months omore.

In a particular embodiment, the non-aqueous liquid compositionsdisclosed herein do not exhibit 10% or more nimodipine degradation overat least a three month period when exposed to 25° C. and 60% relativehumidity and more particularly, about 9% or more, about 8% or more,about 7% or more, about 6% or more, about 5% or more, about 4% or more,about 3% or more, about 2% or more, about 1% or more. In a particularembodiment, the non-aqueous liquid compositions disclosed herein do notexhibit about 1.0% or more nimodipine degradation over at least a threemonth period when exposed to 25° C. and 60% relative humidity and moreparticularly, about 0.9% or more, about 0.8% or more, about 0.7% ormore, about 0.6% or more about 0.5% or more, about 0.4% or more, about0.3% or more, about 0.2% or more, about 0.1% or more or about 0.01% ormore.

One particular nimodipine degradation product that can be minimizedusing the non-aqueous liquid compositions of the present invention isnimodipine related compound A.

In one embodiment, the non-aqueous liquid composition comprises 1.2% orless nimodipine related compound A over at least a three month periodwhen exposed to 25° C. and 60% relative humidity, or more particularly,about 1.2% or less, about 1.1% or less, about 1.0% or less, about 0.9%or less or about 0.8% or less nimodipine related compound A.

In one embodiment, the non-aqueous liquid composition comprises 0.6% orless nimodipine related compound A over at least a three month periodwhen exposed to 25° C. and 60% relative humidity.

In one embodiment, the non-aqueous liquid composition comprises 0.5% orless nimodipine related compound A over at least a three month periodwhen exposed to 25° C. and 60% relative humidity, and more particularly,0.4% or less, 0.35% or less, 0.30% or less, 0.25% or less, 0.20% orless, 0.15% or less, 0.10% or less or 0.05% or less nimodipine relatedcompound A.

In certain embodiments, the non-aqueous liquid composition comprisesfrom 0.01% to about 0.35% nimodipine related compound A over at least athree month period when exposed to 25° C. and 60% relative humidity,such as, for example, from about 0.01% to about 0.30%, about 0.01% toabout 0.25%, about 0.01% to about 0.20%, about 0.01% to about 0.15%,about 0.01% to about 0.10%; about 0.1% to about 0.35%, about 0.10% toabout 0.30%, about 0.10% to about 0.25%, about 0.10% to about 0.20% orabout 0.10% to about 0.15% nimodipine related compound A.

In a particular embodiment, the non-aqueous liquid composition containsabout 95% or less, about 90% or less, about 85% or less, about 80% orless, about 75% or less, about 70% or less, about 65% or less, about 60%or less, about 55% or less, about 50% or less, about 45% or less, about40% or less, about 35% or less, about 30% or less, about 25% or less,about 20% or less, about 15% or less or about 10% or less nimodipinerelated compound A than NYMALIZE® over at least a three month periodwhen exposed to 25° C. and 60% relative humidity,

In another particular embodiment, the non-aqueous liquid compositioncontains between about 50% and about 100% less, between about 50% andabout 95% less, between about 50% and about 85% less, between about 50%and about 80% less, between about 50% and about 75% or between about 50%and about 70% or less nimodipine related compound A than NYMALIZE® overat least a three month period when exposed to 25° C. and 60% relativehumidity.

In one embodiment, the non-aqueous liquid composition containssubstantially no nimodipine related compound A over at least a threemonth period when exposed to 25° C. and 60% relative humidity.

In one embodiment, the total impurities in non-aqueous liquidcompositions of the present invention comprises less than about 1.8%over at least a three month period when exposed to 25° C. and 60%relative humidity, such as, for example, about 1.6% or less, about 1.4%or less, about 1.2%, about 1.0% or less, about 0.8% or less, about 0.6%or less, about 0.4% or less, about 0.2% or less, about 0.1% or less or0.0% or less total impurities.

In one embodiment, the total impurities in non-aqueous liquidcompositions of the present invention comprises less than about 0.7%over at least a three month period when exposed to 25° C. and 60%relative humidity, such as, for example, about 0.5% or less or about0.3% or less, and more particularly, less than about 0.6%, less thanabout 0.5%, less than about 0.4%, less than about 0.3%, less than about0.2%, less than about 0.1%, less than about 0.05% or less than about0.01% total impurities.

In one embodiment, the non-aqueous liquid compositions of the presentinvention comprises about 100% or less total impurities than NYMALIZE®over at least a three month period when exposed to 25° C. and 60%relative humidity,

In one embodiment, the non-aqueous liquid compositions of the presentinvention comprises about 95% or less total impurities than NYMALIZE®over at least a three month period when exposed to 25° C. and 60%relative humidity, such as, e.g., about 90% or less, about 85% or less,about 80% or less, about 75% or less, about 70% or less, about 65% orless, about 60% or less, about 55% or less, about 50% or less, about 45%or less, about 40% or less, about 35% or less, about 30% or less, about25% or less, about 20% or less, about 15% or less, about 10% or lessabout 5% or less total impurities.

In one embodiment, the non-aqueous liquid compositions of the presentinvention comprises substantially no total impurities over at least athree month period when exposed to 25° C. and 60% relative humidity.

In one embodiment, the non-aqueous liquid composition is packaged as asingle dosage unit. In an alternate embodiment, the non-aqueous liquidcomposition is packaged in a container containing multiple dosage units,e.g., a bottle. The non-aqueous liquid composition can be dispensed, forexample, by loading into an automated medication dispensing system, byextraction with an oral dosing device, such as a cup or syringe, or bypouring the composition directly into a device (e.g., a syringe ormachine) for administration to a patient. Other means for providing,preparing, storing, transporting, and dispensing pharmaceuticalcompositions are known to those skilled in the art.

In one embodiment, the shelf life of the non-aqueous liquid compositionis increased relative to compared with NYMALIZE®. The shelf-life of adrug is generally defined as the length of time a drug can stay on theshelf without degrading to unacceptable levels of chemical potency orpharmaceutical utility. Shelf-life may be determined by any suitablemethod.

In a particular embodiment, the shelf life of the non-aqueous liquidcomposition is increased by about 5%, about 10%, about 15%, about 20%,about 25%, about 30%, about 35%, about 40%, about 45%, about 50% ormore.

In another particular embodiment, the shelf life of the non-aqueousliquid composition is increased by about one week, about two weeks,about three weeks, about four weeks, up to one month, up to 2 months, upto 3 months, up to 4 months, up to 5 months, up to 6 months or more than6 months.

In one embodiment, the shelf life of the non-aqueous liquid when it iscontained in a suitable container exhibits a shelf life of at least 6month, more preferably at least 12 months, still more preferably atleast 15 months, yet more preferably at least 18 months, most preferablyat least 21 months and in particular at least 24 months. In oneembodiment, the shelf-life is greater than 24 months, e.g., 26 months,28 months, 30 months or more.

In one embodiment, the shelf life of the non-aqueous liquid when it iscontained in a suitable container container exhibits a shelf life underambient conditions of at least 6 month, more preferably at least 12months, still more preferably at least 15 months, yet more preferably atleast 18 months, most preferably at least 21 months and in particular atleast 24 months. In one embodiment, the shelf-life is greater than 24months, e.g., 26 months, 28 months, 30 months or more.

III. Methods

The present invention provides a method of treating a disorder, orsymptoms associated with a disorder, for which nimodipine provides atherapeutic effect. Nimodipine acts as a vasodilator and is consideredto be a calcium channel blocker, and was approved by the FDA to improveneurological outcome after subarachnoid hemorrhage (SAH) from rupturedblood vessels in the brain.

Accordingly, the present invention provides a method of improvingneurological outcome by reducing the incidence and severity of ischemicdeficits in patients with subarachnoid hemorrhage from rupturedintracranial berry aneurysms comprising administering to a patient inneed thereof an effective amount of a non-aqueous liquid compositioncomprising nimodipine described supra.

The non-aqueous liquid composition is preferably administered enterally.Suitable enteral administration routes include, but are not limited to,oral, via nasogastric tube or via gastric tube. In a particularembodiment, the non-aqueous liquid composition is administered to thepatient via nasogastric tube.

A dosage unit of the non-aqueous liquid composition is firstadministered after the subarachnoid hemorrhage, such as, for example,within about 100 hours of the subarachnoid hemorrhage, within about 90hours of the subarachnoid hemorrhage, within about 80 hours of thesubarachnoid hemorrhage, within about 70 hours of the subarachnoidhemorrhage, within about 60 hours of the subarachnoid hemorrhage, withinabout 50 hours of the subarachnoid hemorrhage, within about 40 hours ofthe subarachnoid hemorrhage, within about 30 hours of the subarachnoidhemorrhage, within about 20 hours of the subarachnoid hemorrhage, withinabout 10 hours of the subarachnoid hemorrhage or within about 5 hours ofthe subarachnoid hemorrhage. In a particular embodiment, a dosage unitof the non-aqueous liquid composition is administered within about 96hours of the subarachnoid hemorrhage.

A dosage unit of the non-aqueous liquid composition can be administeredto the patient once a day or multiple times a day, such as, for example,twice or more per day, three times or more per day, four times or moreper day, five times or more per day or six times or more per day.

A dosage unit of the non-aqueous liquid composition can be administeredin various intervals, such as, for example, every two hours, every fourhours, every six hours, every eight hours, every 12 hours or every 24hours. In a particular embodiment, a dosage unit of the non-aqueousliquid composition is administered to the patient every four hours.

The duration of treatment can vary. In one embodiment, treatment iscontinued for at least 7 days, at least 14 days, at least 21 days or atleast 30 days. In a particular embodiment, the dosing regimen iscontinued for 21 days.

In exemplary embodiments, a dosage unit of the non-aqueous liquidcomposition is administered every four hours for 21 days. The firstdosage unit is administered within 96 hours of the subarachnoidhemorrhage. The dosage unit preferably comprises 60 mg nimodipine.

The non-aqueous liquid composition can be dosed before or after feeding.In one embodiment, a dosage unit is administered about 1 hour prior to ameal. In another embodiment, a dosage unit is administered about twohours after a meal.

The present invention also provides a method of treating otherconditions including, but not limited to, vasospastic angina,Prenzmetal's angina, stable angina, acute myocardial infarction,myocardial arrest, arrhythmia, systemic hypertension, pulmonaryhypertension, congestive heart failure, and hypertrophic cardiomyopathycomprising administering to a patient in need thereof an effectiveamount of a non-aqueous liquid composition comprising nimodipinedescribed supra.

In a particular embodiment, the method of the present invention isassociated with decreased instances of diarrhea compared to NYMALIZE,i.e., about 100%, about 90%, about 80%, about 70%, about 60%, about 50%,about 40%, about 30%, about 20%, about 10% decrease in instance measuredover the period of a day, week or month.

EXAMPLES Example 1: Stability Study

Two non-aqueous liquid compositions of the present invention werecompared to NYMALIZE® over the course of a 3-month accelerated stabilitystudy. The non-aqueous liquid compositions were prepared with thefollowing ingredients:

A. Formulation A (2017NIM009)

A 10 liter batch was prepared with the ingredients shown in Table 1,below. The pH of the batch was adjusted to within pH 6 to 7 with 6N HCland 6N NaOH after completion.

TABLE I Formula A (2017NIM009) Material % W/V Theoretical Amount (g)Actual Amount (g) Nimodipine 0.60 60.00 60.06 PEG 400 68.00 6,800.006,806.64 Ethanol 95% 0.395 39.50 39.51 Glycerin 47.505 4,750.50 4,757.62Total 116.5 11,650.00 11,663.83B. Formulation B (2017nim010)

A 10 liter batch was prepared with the ingredients shown in Table II,below.

TABLE II Formula B (2017NIM010) Material % W/V Theoretical Amount (g)Actual Amount (g) Nimodipine 0.60 60.00 60.00 PEG 400 68.00 6,800.006,800.54 Ethanol 95% 0.395 39.50 39.52 Glycerin 47.505 4,745.25 4,750.09Benzoic Acid 0.0375 3.75 3.75 Sodium 0.015 1.50 1.50 Benzoate Total116.5 11,650.00 11,655.40

C. Formulation C (2017NIM013)

A 5 liter batch was prepared with the ingredients shown in Table III,below:

TABLE III Formulation C (2017NIM013) Material % W/V Theoretical Amount(g) Actual Amount (g) Nimodipine 0.60  30.00 30.00 PEG 400 68.00 3400.003410.00 Ethanol 95% 0.395  19.975 19.78 Glycerin 47.505 2375.25 2374.33Methylparaben 0.20  10.00 10.00 Total 116.7 5835.00 (5000 mL) 5844.11

Samples of all three compositions were stored at 40° C. and 75% relativehumidity (RH). The amount of nimodipine present in the same was measuredat one month, two month and three month time points by HPLC. Formationof degradants (“related substances”) and nimodipine related compound A(NRCA) were also measured by HPLC at the same time points. The resultsof the study are shown in Table IV, below:

TABLE IV Amount of Nimodipine/Formation of Degradants Over Time forNYMALIZE ® and Formulations A, B and C stored at 40° C. and 75% RH TimePeriod/Storage Formulation A Formulation B Formulation C Test ConditionNYMALIZE ® (2017nim009) (2017nim010) (2017nim013) Assay Initial 100.1101.7 102.4 103.9 (% LC) 1 month 40/75 98.5 103.4 102.9 101.1 2 month40/75 97.5 100.2 100.5 100.1 3 month 40/75 96.0 100.1 99.4 101.5 6 month40/75 92.1 100.1 97.8 99.9 Total Initial ND ND 0.1 ND Impurities 1 month40/75 0.80 0.21 0.51 0.10 2 month 40/75 1.40 0.45 0.69 0.13 3 month40/75 2.10 0.99 0.77 0.40 6 month 40/75 3.0 1.5 1.9 ND Compound InitialND ND 0.1 ND A 1 month 40/75 0.8 0.2 0.5 0.1 2 month 40/75 1.4 0.5 0.70.1 3 month 40/75 2.1 1.0 0.8 0.4 6 month 40/75 3.0 1.5 1.9 ND ND = notdetected

Samples of all three compositions were stored at 25° C. and 60% relativehumidity (RH). The amount of nimodipine present in the same was measuredat one month, two month and three month time points by HPLC. Formationof degradants (“related substances”) and nimodipine related compound A(NRCA) were also measured by HPLC at the same time points. The resultsof the study are shown below:

TABLE V Amount of Nimodipine/Formation of Degradants Over Time forNYMALIZE ® and Formulations A, B and C stored at 25° C. and 60% RH TimePeriod/Storage Formulation A Formulation B Formulation C Test ConditionNYMALIZE ® (2017nim009) (2017nim010) (2017nim013) Assay Initial 100.1101.7 102.4 103.9 (% LC) 1 month 25/60 2 month 25/60 101.6 3 month 25/60100.3 100.6 101.6 100.6 6 month 25/60 99.7 101.3 101.7 Total Initial 0.0ND 0.1 ND Impurities 1 month 25/60 ND 2 month 25/60 ND 3 month 25/60 0.5ND ND ND 6 month 25/60 0.7 0.3 0.2 Compound Initial ND ND ND ND A 1month 25/60 2 month 25/60 ND 3 month 25/60 0.4 ND ND ND 6 month 25/600.6 0.1 0.1 ND Blank = ND HPLC methodology for detection of nimodipineand for detection of nimodipine related substances is as follows.

Detection of Nimodipine

An Inertsil ODS-2 150×4.6 mm HPLC column, 5 μm (example part number5020-01124) or equivalent column is used with a C8 or C18 pre-column(example part number Phenomenex AJO-4287 or equivalent). Reagents andsolutions include deionized water (CAS #7732-18-5), HPLC grade methanol(CAS #67-56-1), tetrahydrofuran (THF, CAS #109-99-9) and nimodipinereference standard (CAS #66085-59-4). A 1000 mL mobile phase solutionconsists of 600 mL water, 200 mL methanol and 200 mL tetrahydrofuran.Degas for 10 minutes.

Chromatographic Conditions

-   -   Column: Inertsil ODS-2 150×4.6mm HPLC column, 5 μm, example part        number 5020-01124 (GL Sciences) or equivalent    -   Guard Column: C8 or C18 (example Phenomenex, Cat. No. AJ0-4287)        or equivalent    -   Temperature: 40° C. (Column)    -   Flow Rate: 1.8 mL/minute    -   Detection: Photodiode Array (PDA) detector    -   Injection Volume: 10 μL    -   Run Time: Approximately 45 minutes for Standard injections and        approximately 85 minutes for Sample injections.    -   Pump: Isocratic    -   Elution Time: If methylparaben is present in the formulation,        the retention time (RT) is approximately 3 min. The retention        time of Nimodipine Related Compound A is approximately 15-19        minutes. The retention time of nimodipine is approximately 21-26        minutes.

Use a suitable HPLC system that provides comparable resolution,reproducibility, and sensitivity. Due to differences in columns andinstrumentation, it may be necessary to adjust the mobile phasecomposition and/or instrument parameters to achieve system suitabilityrequirements. Chromatographic parameters are not adversely affected bysmall HPLC parameter changes that could potentially be encountered inthe average laboratory environment or small variations in theperformance associated with HPLC equipment from different vendors.

The mobile phase contains a high concentration of tetrahydrofuran, whichcan lower the burst strength of some plastic materials. It isrecommended that the HPLC lines to and post column are composed ofstainless steel or other resistant materials.

To prepare the working standard solution, accurately weigh approximately60 mg of Nimodipine Reference Standard into a 50 mL actinic volumetricflask. Add 10 mL THF and sonicate 10 minutes to dissolve Bring to volumewith mobile phase: Mix well.

Accurately weigh approximately 20 mL of sample solution into a lowactinic 50 mL volumetric flask. Add 10 mL of THF and shakemechanistically (for example, wrist-action shaker) for 5 minutes. Diluteto volume with mobile phase. Store at 4° C. (2-8° C.). Concentration isapproximately 1.2 mg/mL nimodipine.

Due to differences in columns and instrumentation, it may be necessaryto adjust the mobile phase composition and/or instrument parameters toachieve system suitability requirements. Chromatographic parameters arenot adversely affected by small HPLC parameter changes that couldpotentially be encountered in the average laboratory environment orsmall variations in the performance associated with HPLC equipment fromdifferent vendors. Please note that the nimodipine HPLC run needssufficient time to equilibrate. It is recommended that multiple workingstandard injections be performed for equilibration prior to analysis.Inject the Nimodipine Working Standard Solution. Inject a blank solutionof mobile phase to prevent possible carry-over. Inject the NimodipineSample Preparation. The absorption spectrum of the preparation of thetest specimen containing nimodipine exhibits maxima only at the samewavelengths as that of a similar preparation of the correspondingNimodipine Reference Standard. As the solvents included as part of thesample preparation can contribute to noise at the lower wavelengths, itis recommended that the spectrum comparison be performed between 220-400 nm.

Detection of Nimodipine Related Substances

An Inertsil ODS-2 150×4.6 mm HPLC column, 5 μm (example part number5020-01124) or equivalent column is used with a C8 or C18 pre-column(example part number Phenomenex AJO-4287 or equivalent). Reagents andsolutions include deionized water (CAS #7732-18-5), HPLC grade methanol(CAS #67-56-1), tetrahydrofuran (THF, CAS #109-99-9), 3% hydrogenperoxide and nimodipine reference standard (CAS #66085-59-4). A 1000 mLmobile phase solution will consist of 600 mL water, 200 mL methanol and200 mL tetrahydrofuran. Degas for 10 minutes.

Chromatographic Conditions

-   -   Column: Inertsil ODS-2 150×4.6mm HPLC column, 5 μm, example part        number 5020-01124 (GL Sciences) or equivalent    -   Guard Column: C8 or C18 (example Phenomenex, Cat. No. AJ0-4287)        or equivalent    -   Temperature: 40° C. (Column)    -   Flow Rate: 1.8 mL/minute    -   Detection: UV absorbance at 271 nm.    -   Injection Volume: 10 μL    -   Run Time: Approximately 45 minutes for Standard injections and        approximately 85 minutes for Sample injections.    -   Pump: Isocratic    -   Elution Time: If methylparaben is present in the formulation,        the retention time (RT) is approximately 3 min. The retention        time of Nimodipine Related Compound A is approximately 15-19        minutes. The retention time of nimodipine is approximately 21-26        minutes.

Use a suitable HPLC system that provides comparable resolution,reproducibility, and sensitivity. Due to differences in columns andinstrumentation, it may be necessary to adjust the mobile phasecomposition and/or instrument parameters to achieve system suitabilityrequirements. Chromatographic parameters are not adversely affected bysmall HPLC parameter changes that could potentially be encountered inthe average laboratory environment or small variations in theperformance associated with HPLC equipment from different vendors.

Please note that the mobile phase contains a high concentration oftetrahydrofuran, which can lower the burst strength of some plasticmaterials. It is recommended that the HPLC lines to and post column arecomposed of stainless steel or other resistant materials.

To prepare the standard solution, accurately weigh approximately 10 mg(+/−1 mg) of nimodipine Related Compound A Reference Standard into a 50mL actinic volumetric flask. Add 5 mL THF and sonicate 10 minutes todissolve. Bring to volume with mobile phase. Dilute to volume withmobile phase. Mix well. Store at 4° C. (Concentration is approximately0.2 mg/mL Related A).

Transfer 3.0 mL of the above stock solution into a 100 mL volumetricflask. Dilute to volume with mobile phase (Concentration isapproximately 0.006 mg/ml Related A, or 0.5% of the analytical sampleconcentration of Nimodipine Related Compound A). Prepare the aboveNimodipine Related Compound A Reference Standard in duplicate. The firstpreparation will be considered the Nimodipine Related Compound A WorkingStandard Solution, and the second preparation will be considered theNimodipine Related Compound A Check Standard Solution.

To prepare the resolution standard solution, accurately weighapproximately 60 mg of Nimodipine Reference Standard into a 50 mLactinic volumetric flask. Add 10 mL THF and sonicate 10 minutes todissolve. Bring to volume with mobile phase: Mix well. Pipette 5.0 mL ofthe above solution into a glass tube or other appropriate heat-resistantcontainer. Add 0.5 mL of the 3% hydrogen peroxide and heat at 90° C. inthe oven for 1 hour. Allow to cool to room temperature. Transferquantitatively into a low actinic 10 mL volumetric flask. Dilute tovolume with mobile phase. Mix well. Store at 4° C. Discard when analysesare complete.

After injecting the Resolution Standard, inject the mobile phase twelvetimes for greater than or equal to one minute each. For the Waters HPLCsystems, diluent may be injected eleven times for 4 minutes each, andonce for 10 minutes prior to injecting standards. The extended run time(extended from a run time of one minute per mobile phase injection) isto allow for equilibration of the baseline after elution of the solventfront and may be altered on a system to system basis. Please note thatthe intent of this preparation is not for quantitation, but to confirmresolution between nimodipine and the peak immediately prior tonimodipine, at RRT 0.9 (wherein RRT stands for Relative Retention Time)

Accurately weigh approximately 20 mL of sample solution into a lowactinic 50 mL volumetric flask. Add 10 mL of THF and shakemechanistically (for example, wrist-action shaker) for 5 minutes. Diluteto volume with mobile phase. Store at 4° C. Concentration isapproximately 1.2 mg/mL nimodipine.

Inject the Nimodipine Resolution Standard. For the Nimodipine ResolutionStandard, Resolution (R) between the unknown peak before nimodipine (RRT0.9) and nimodipine in the resolution solution should be not less that(NLT) 1.0 (R>=1.0). Inject the diluent solution as prescribed above postinjection of the Resolution Standard.

Inject the Nimodipine Related Compound A Working Standard six times. Thepercent relative standard deviation (% RSD) should be less than or equalto 10%. Please note that equilibration injections of the standard may beallowed post the injections of the Nimodipine Resolution standard anddiluent injections.

Inject the Nimodipine Related Compound A Check Standard Solution twotimes. Comparison of the average peak area responses (area per unitweight) (n=2) of the check standard and working standard (n=6) is ±10%.

Inject in duplicate each sample preparation and inject a standard induplicate after every six samples. Quantify the known related compoundsand any additional peaks of unknown individual impurities.

We claim:
 1. A liquid composition, comprising (a) nimodipine as the onlyactive ingredient, wherein the nimodipine is present in the liquidcomposition at a concentration of about 6 mg/mL; (b) polyethyleneglycol, wherein the polyethylene glycol is present in the liquidcomposition in an amount of about 50% to about 75% (w/v); (c) glycerin,wherein the glycerin is present in the liquid composition in an amountof about 25% to about 60% (w/v); wherein about 5% or less nimodipinedegradation is observed over a period of at least six months whenexposed to 40° C. and 75% relative humidity, and wherein the liquidcomposition is formulated for enteral administration.
 2. The liquidcomposition of claim 1, wherein the polyethylene glycol is present inthe liquid composition in an amount of about 60% to about 70% (w/v). 3.The liquid composition of claim 1, wherein the glycerin is present inthe liquid composition in an amount of about 40% to about 50% (w/v). 4.The liquid composition of claim 1, further comprising ethanol.
 5. Theliquid composition of claim 4, wherein the ethanol is 95% ethanol. 6.The liquid composition of claim 4, wherein the ethanol is present in theliquid composition in an amount of about 1% or less by weight.
 7. Theliquid composition of claim 1, further comprising water.
 8. The liquidcomposition of claim 7, wherein the water is present in the liquidcomposition in an amount of about 1% or less by volume.
 9. The liquidcomposition of claim 1, further comprising a buffer agent.
 10. Theliquid composition of claim 1, further comprising a parabenpreservative.
 11. A method of improving neurological outcome by reducingthe incidence and severity of ischemic deficits in patients withsubarachnoid hemorrhage from ruptured intracranial berry aneurysmscomprising enterally administering to a patient in need thereof aneffective amount of the liquid composition of claim
 1. 12. The method ofclaim 11, wherein the liquid composition is administered orally, vianasogastric tube or via gastric tube.
 13. The method of claim 11,wherein a first unit dose of the liquid composition is administered tothe patient within about 100 hours of the subarachnoid hemorrhage. 14.The method of claim 11, wherein the liquid composition is administeredabout every four hours.